Unifying perspectives on the activity and genotypic targeting of pharmacological chaperones

Several diseases of protein misfolding can now be treated with an emerging class of therapeutics known as pharmacological chaperones, pharmacochaperones, or correctors. These small molecules exploit the universal thermodynamic coupling between ligand binding and protein folding to suppress conformational defects that disrupt protein homeostasis. While the mechanistic basis of their activity is quite simple in theory, their nuanced proteostatic effects can vary depending on the intrinsic properties of their target proteins and the cellular context. Deviations in activity are especially pronounced across panels of pathogenic variants of the target protein. In this perspective, we explore the factors that shape the potency of pharmacochaperones and the intrinsic sensitivity of different target proteins in relation to various theoretical considerations and experimental observations. We discuss how emerging technologies have provided general insights into the molecular basis of the variant-specific effects of certain pharmacochaperones. We also highlight ongoing efforts to identify existing drugs that stabilize misfolded variants and to repurpose them as pharmacochaperones. Finally, we discuss how the chaperone activity of current drugs could potentially contribute to complex pharmacology and deviations in therapeutic efficacy across patient cohorts. Together, these principles provide a coherent framework that may help guide the discovery and precision targeting of next-generation pharmacochaperones for both current and new targets involved in proteostasis diseases. An audio recording of this work is included in the supplement and can be freely streamed here.